2-hydroxymethyl-delta2-androsten derivatives and process



United States Patent Ofitice 3,055,920 Patented Sept. 25, 1962 3,055,9202-HYDR0XYMETHYL-A -ANDRSTEN TIVES AND PROCESS Albert Bowers, JohnEdwards, and James C. Orr, all of exico City, Mexico, assignors, bymesne assignments, to Syntex Corporation, a corporation of Panama NoDrawing. Filed Oct. 20, 1961, Ser. No. 146,455 Claims priority,application Mexico Feb. 23, 1961 17 Claims. (Cl. 260-397.5)

DERIVA- powerful anabolic agents having a favorable anabolic-androgenicratio; they help to increase the protein metabolism and the depositionof calcium on the bone tissue; furthermore they show antiestrogenicactivity, lower the cholesterol level in the blood and inhibit thesecretion of gonaldotropins by the pituitary gland. The flee-alkenyl andNoe-alkynyl compounds further exhibit progestational activity.

The novel compounds object of our invention are represented by thefollowing formula:

WORM-L 1'1 In the above formula R represents hydrogen or methyl; Rrepresents hydrogen or an acyl group derived from a carboxylic acid of lto 12 carbon atoms; R represents hydrogen, an alkyl, alkenyl or alkynylgroup such as methyl, ethyl, propyl, vinyl, ethynyl or propynyl, and Rrepresents hydrogen, a lower alkyl group, a lower aralkyl group of 1 to8 carbon atoms or an acyl radical derived from a carboxylic acid of 1 to12 carbon atoms.

The acyl groups set forth above derive from carboxylic acids of lessthan 12 carbon atoms, saturated or unsaturated, of straight, branched,cyclic or mixed aliphaticcyclic chain, substituted or not with groupssuch as hydroxy, methoxy, amino, halogen or other groups; typical suchesters are the acetate, propionate, butyrate, valerate, hemiscuccinate,enanthate, caproate, benzoate, undecenoate, trimethylacetate,phenoxyacetate, cyclopentylpropionate and B-chloropropionate.

The novel compounds object of our invention are obtained from the2-formyl-l7fl-hydroxy-A -androstenes and the corresponding l9-norderivatives.

In our copending patent application Serial No. 128,974, filed August 3,1961, there is described the preparation of the Z-forrnyl-M-androstenesstarting from a 2-alkoxymethylene derivative of dihydroallotestosterone,19-nordihydroallotestosterone or one of the 17a-alkyl, alkenyl oralkynyl substituted derivatives, which by reduction with a double metalhydride furnish the corresponding 3- hydroxy derivatives. By acidtreatment of these compounds in the presence of a proton acceptor thereare obtained the 2-formyl-A -androstenes.

By reduction of 2-formyl-A -androsten-175-01, or of the 17m-alkyl,alkenyl or alkynyl substituted derivatives, as Well as of thecorresponding l9-nor derivatives, there are obtained the respectiveZ-hydroxymethyl compounds, which upon subsequent esterification producethe corresponding monoor di-esters.

The treatment of the l7-esters of 2-hydroxymethyl-A androsten-17fi-ol,2-hydroxymethyl-l9-n0r-A -androsten- 1713-01 or of the Not-substitutedderivatives with an etherifying agent gives rise to the formation of the2- alkoXy and 2-aralkoxy compounds.

The method described above for preparing the 2-hydroxymethyl and2-acyloxymethyl derivatives is illustrated by the following sequence ofreactions:

on OH |---R9 ---R R i i R ono- Homo- I m I H r a II R mongo- 1'1 III Inthe above formulas R, R and meaning as set forth above; R of less than12 carbon atoms.

In practicing the process outlined above, Z-formyI-A androsten-17,8-olor one of the Not-substituted derivatives thereof (I; R=Me) is subjectedto reduction with a double metal hydride, such as sodium borohydride orpotassium borohydride, in a solvent inert to the reaction, such asmethanol, tetrahydrofuran 0r dioxane, at room temperature for aprolonged period of time or under reflux for 1 hour, to produce thecorresponding 2-hydroxymethyl derivatives (II, R=Me). Esterification ofsuch compounds with anhydrides or chlorides derived from carboxylicacids of 1 to 12 carbon atoms, in pyridine or benzene solution, producesthe 2,17-diesters (III; R=Me, R =hydrogen) or 2-monoesters (III; R=Me, R=alkyl, alkenyl or alkynyl). The (3-2 monoesters may be esteritied atC-17 with the same or a different acid anhydride or chloride ofhydrocarbon carboxylic acids of less than 12 carbon atoms, in benzenesolution and in the presence of p-toluenesulfonic acid.

In the same manner, the process described above is applied to theZ-formyl-19-nor-A -androstenes, thus producing Z-hydroxymethyl-19-nor-A-androsten-17,8-01 and the corresponding 17a-alkyl, alkenyl and alkynylderivatives, as well as the monoand diesters of such compounds.

Alternatively, there maybe employed as starting material and ester of2-formyl-A -androsten--01, of 2- formyl-19-nor-A -androsten-l7B-ol or ofthe corresponding Nix-substituted derivatives, which on reduction with adouble alkali metal hydride in dioxane or tetrahydrofuran underanhydrous conditions, to avoid hydrolysis of the acyloxy groups, producethe corresponding 17- esters of 2'-hydroXymethy1-17fi-hydroXy-A-andr0stenes and l9-nor-androstenes.

The novel 2-alkoxy and 2-aralkoxy compounds object R have the samerepresents and acyl radical of our invention are obtained by the methodillustrated by the following sequence of reactions:

In the above formulas R, R and R have the same meaning set forthpreviously; R represents a lower alkyl or aralkyl group containing up to8 carbon atoms.

In practicing the process just outlined, a l7-ester of 2-hydroxymethyl-A-androsten-175-01, which may further possess a substituent at Cl7oc ofthe type set forth above, or from the corresponding 19-nor derivatives(IV), is allowed to react at room temperature with an excess of an ethersolution of a diazoalkane, such as diazomethane or diazoethane, and inthe presence of a catalyst, such as boron trifluoride or aluminumchloride, to produce the Z-methoxymethyl or 2-ethoxymethyl derivatives(V; R ==methyl, ethyl). Saponification of these compounds byconventional methods produces the corresponding free ethers (VI; R=methyl, ethyl).

Alternatively, the etherification may be effected by reacting at thereflux temperature the 2-hydroxymethyl compounds of Formula IV with analkyl or aralkyl halide, preferably with an alkyl or aralkyl iodide, inan organic solvent such as acetone and in the presence of a base, suchas potassium carbonate, or by treatment with an alkyl sulfate in acetonesolution and in the presence of a base, preferably potassium hydroxide,at room temperature.

' The following examples serve to illustrate but are not intended tolimit the present invention.

Example I A solution of 5 g. of Z-formyl-M-androsten-17 3-01 in 200 cc.of methanol was cooled to 5 C., treated with 1.5 g. of sodiumborohydride in 30 cc. of methanol and the mixture was kept at roomtemperature for 1 hour under anhydrous conditions; at the end of thistime it was cooled, the excess of reagent was destroyed with a few dropsof glacial acetic acid and water wa added until complete precipitation;the precipitate formed was collected by filtration, washed and dried,thus yielding 2-hydroxymethyl-A -androsten-175-01; M.P. 193194 C., [ethl-65 (chloroform).

A mixture of 1 g. of the above compound, 4 cc. of pyridine and 2 cc. ofacetic anhydride was heated on the steam bath for 1 hour, poured intowater and the precipitate formed was collected, washed with water toneutral and dried. By crystallization from acetonehexane there wasobtained 2-acetoxymethyl-A androsten- 175-01 acetate.

Example 11 By following the method of the preceding example, but using2-formyl-19-nor-A -androsten-173-01 as starting 4 material, there wasobtained 2-hydroxymethyl-19-nor-A androsten-17B-ol and its correspondingdiacetate.

Example 111 To a solution of 10 g. of 2-formyl-17a-methyl-A-androsten-17l3-ol in 300 cc. of anhydrous tetrahydrofuran was added 10g. of sodium borohydride and the mixture was stirred at room temperaturefor 24 hours; at the end of this time the excess of reagent wasdestroyed with acetic acid, poured into ice water and the precipitatewas collected. Crystallization from acetone-ether afforded 2-hydroxymethyl 17a methyl A -androsten-17B-ol; M.P. 167169 C.; [a] +26(chloroform).

In another experiment there was employed anhydrous dioxane as solvent,with the same result.

A mixture of 1 g. of Z-hydroxymethyl-17a-methyl-A androsten-17fl-ol, 10cc. of pyridine and 1 cc. of acetyl chloride was kept at roomtemperature for 36 hours and then the solvent was evaporated undervacuum at a temperature below 60 C. Crystallization of the residue frommethylene chloride-hexane furnished 2-acetoxymethyl-17ot-methyl-A-androsten-175-01.

Example IV In accordance with the method of reduction described in thepreceding example, there was treated 5 g. of 2- formyl-17a-ethyl-A-androsten-175-01 with sodium borohydride using tetrahydrofuran assolvent, thus yielding 2- hydroxymethyl-l7a-ethyl-A -androsten-176-01.

From a solution of 1 g. of the above compound in cc. of benzene free ofthiophene there was distilled approximately 30 co. in order to removemoisture; there was then added 0.52 cc. of pyridine and 1.5 cc. ofundecenoyl chloride and the mixture was refluxed for 1 hour; afterevaporating to dryness under vacuum the residue was chromatographed on30 g. of washed alumina, thus yielding Z-undecenoyloxymethyl-17a-ethyl-A-androsten-17fi-ol.

Example V By following the method of reduction described in Example I,2-formyl-17a-ethynyl-A -andr0sten-175-01, 2- formyl-l7a-vinyl-A-androsten--01, 2-formy1-17a-vinyl- 19-nor-A -androsten-17fl-ol and2-formyl-17a-ethynyl-19- nor-A -androsten-17B-ol were respectivelyconverted into 2-hydroxymethyl-17a-ethynyl-d -androsten-1713-01,2-hydroxymethyl 17u-vinyl-A -androsten-17,8-01, Z-hydroxymethyl 17avinyl-19-nor-A -androsten-17,6-01 and2-hydroxymethyl-17wethynyl-19-nor-A -androsten-175-01.

Example VI A solution of 500 mg. of 2-hydroxymethyl-A -androsten-17B-olin 2 cc. of pyridine was treated with 1 cc. of caproic anhydride and themixture was kept overnight at room temperature; it was then poured intowater and the precipitate formed was collected by filtration, thusaffording the caproate of 2-capronoxyrnethyl-A androsten-17fi-ol.

By the same method, but using propionic, valeric andcyclopentylpropionic anhydride as esterifying agents, there wereobtained the corresponding diesters of 2-hydroxymethyl-A-androsten-175-01.

Example VII A mixture of 1 g. of 2-hydroxymethyl-17a-methyl-Aandrosten-l7i-3-ol, 50 cc. of benzene, 2 cc. of acetic anhydride and 500mg. of p-toluenesulfonic acid was kept at room temperature for 48 hoursand then diluted with water; the benzene layer was separated,consecutively washed with 5% sodium carbonate solution and with water toneutral, dried over anhydrous sodium sulfate and evaporated to drynessunder reduced pressure. By chromatography of the residue andcrystallization of the solid fractions from acetone-ether there wasobtained the agetatle of 2 acetoxymethyl-17a-rnethyl-A -androsten- Inthe same manner, but employing propionic, caproic, undecenoic andcyclopentylpropionic anhydrides as esterifying agents (the latter twobeing employed in twice the amount), there were obtained the propionateof Z-propionoxymethyl-l7a-methyl-A -androsten-17,6-01, the caproate of 2capronoxymethyl 17a-methyl-A -and-rosten-175-01, the undecenoate ofZ-undecenoyloxymethyl-l7a-methyl- A -androsten-17 3-ol and thecyclopentylpropionate of 2- cyclopentylpropionoxymethyl 17a-methyl-A-androsten- Example VIII 2 g. of 2-formyl-Not-methyl-19-nor-A-androsten-17 8-01 was reduced with sodium borohydride intetrahydrofuran, following the method described in Example I; there wasthus obtained 2-hydroxymethyl-17u-methyl-l9-nor-A androsten-17/8-ol.

The above compound was dissolved in 10 cc. of pyridine and 5 cc. ofacetic anhydride, heated for 1 hour on the steam bath and poured intoice water; the precipitate formed was collected, thus givingZ-acetoxy-methyl- Hot-methyl-19-nor-A -androsten-l75-01.

500 mg. of the latter compound was treated with 1 cc. ofcyclopentylpropionic anhydride in benzene solution and in the presenceof p-toluenesulfonic acid, in accordance with the method described inExample VII; there was thus obtained the cyclopentylpropionate of2-acetoxymethyll7a-methyl-19-nor-androsten-17 3-01.

Example IX A mixture of 5 g. of Z-formyl-17a-methyl-A -androsten-17,8-01, 200 cc. of acetic acid, 100 cc. of acetic anhydride and 5 g. ofp-toluenesulfonic acid was kept at room temperature for 1 hour, pouredinto water, stirred for 30 minutes to hydrolyze the excess of anhydrideand ex tracted several times with methylene chloride; the combinedextract was washed to neutral, dried over anhydrous sodium sulfate andevaporated to dryness. The residue was dissolved in 100 cc. of 1%methanolic potassium hydroxide, kept at -10 C. for 1 hour, poured intoWater and extracted with ethyl acetate; the extract was washed withwater to neutral, dried over anhydrous sodium sulfate and evaporated todryness under vacuum. By crystallization from acetone-hexane there wasobtained the acetate of 2-formyl-17m-mcthyl-n -androsten-l7,8-01.

The above compound was reduced with sodium borohydride intetrahydrofuran, in accordance with the method of Example III, toproduce the acetate of 2-hydroxymethyl-1 7a-methyl-A -androsten-175-01.

By the same method 2-formyl-17a-ethyl-A -androsten- 17 8-01 wasconverted into the respective acetate which on reduction afforded theacetate of 2-hydroxymethyl-17aethyl-A -androsten-175-01.

Example X A solution of 1 g. of the acetate of Z-hydroxymethyl-17a-methyl-A -androsten-17,8-01 in 100 cc. of ether was cooled to 0-5 C.and treated with an ether solution of diazomethane (prepared from g. ofnitrosomethylurea) and 3 drops of recently distilled boron trifluorideetherate. The mixture was kept at room temperature for 1 hour, treatedwith a few drops of acetic acid to destroy the excess of diazomethaneand then evaporated to dryness; there was thus obtained2-methoxymethyl-17a-methyl-A androsten-lZB-ol, acetate.

A solution of 500 mg. of the above compound in 50 cc. of methanol wastreated with 500 mg. of potassium hydroxide dissolved in 1 cc. of waterand 5 cc. of methanol and the mixture was kept overnight at roomtemperature; it was then neutralized with acetic acid, concentrated to asmall volume and diluted with water until complete precipitation. Theproduct was collected by filtration and crystallized from methylenechloride-hexane, thus affording 2-methoxymethyl-l7a-methyl-A-androsten-17/3-01.

- sten-17/3-o1 as starting material.

Example XI To a solution of 10 g. of 2-formyl-A -androsten-17fl-ol in 40cc. of pyridine was added 10 cc. of benzoyl chloride and the mixture washeated on the steam bath for 1 hour, cooled and poured into water; theprecipitate formed was collected and recrystallized fromchloroform-methanol, thus yielding the benzoate of 2-formyl-A-androsten- 17,6-01.

To a solution of 5 g. of the above benzoate in cc. out anhydrous dioxanewas added 5 g. of potassium borohydride and :the mixture was stirredovernight at room temperature and under anhydrous conditions; the excessof reagent was destroyed with acetic acid, the mixture was poured intowater and the product extracted with ethyl acetate. The organic extractwas washed to neutral, dried and evaporated to dryness under vacuum.Crystallization from chloroform-methanol furnished the benzoate of2-hydroxymethyI-A -androsten--01.

By subsequent treatment with an excess of diazomethane, in accordancewith the method of Example X, there was obtained the benzoate of2-methoxymethyl-A -andosten-17fl-ol. a

A solution of 500 mg. of the above compound in 25 cc. of 2% methanolicpotassium hydroxide solution was refluxed for 2 hours, then neutralizedwith acetic acid, concentrated under vacuum to a small volume and pouredinto ice cold salt water; the precipitate formed was col lected, washedand dried, thus giving 2-methoxymethyl- A -androsten-17,B-ol.

Example XII There was repeated the process of the preceding example, butusing the acetate of 2-formyl-19-nor-A -andro- There were thussuccessively obtained: the acetate of 2-hydroxymethyl-19- nor-A-androsten-17/8-ol, the acetate of 2-methoxymethyl- 19-nor-A-androsten-17a-o1 and 2-methoxymethyl-19-nor- A -androsten-l7-ol.

Example XIII 1 g. of the caproate of Z-formyl-17a-vinyl-A-androsten-17fl-ol was reduced with sodium borohydride in dioxanesolution, in accordance with the method of Example III, to produce thecaproate of 2-hydroxymethyl-17avinyl-n -androstend7,8-01.

A solution of 500 mg. of the above compound in 75 cc. of ether wastreated with an ether solution of diazomethane and 10 mg. of aluminumchloride; the mixture was kept at room temperature for 1 hour, theexcess of diazomethane was destroyed by the addition of a few drops ofacetic acid and evaporated to dryness, thus furnishing the caproate ofZ-methoxymethyl-17a-vinyl-A androsten-17fi-ol.

Example XIV There was repeated the method of Example X, but employing anether solution of diazoethane instead of diazomethane, thus obtainingthe acetate of 2-ethoxymethyll7a-methyl-A -androsten-175-01 and then thecorrespond ing free compound.

Example XVI A mixture of 2 g. of the acetate of Z-hydroxymethyl-17a-methyl-A -androsten-175-01, 100 cc. of anhydrous acetone, 10 cc. ofmethyl iodide and 2 g. of anhydrous ethynyl f 19 nor A andro-' potassiumcarbonate was refluxed for 48 hours. At the end of this time it waspoured into water, extracted with ethyl acetate and the organic extractwas washed with water, dried over anhydrous sodium sulfate andevaporated to dryness under vacuum. The residue was purified bychromatography on washed alumina, thus furnishing the acetate of2-methoxymethyl17a-methy1-A androsten-17/3-ol, identical with theproduct obtained in Example X.

Example XVII By following the method of the preceding example, but usingethyl, propyl or benzyl iodide instead of methyl iodide, the acetate of2-hydroxymethyl-17u-ethyl-A -androsten-17B-ol was converted into2-ethoxymethyl-17aethyl-A -androsten-17B-ol acetate,2-propoxymethyl-l7aethyl-M-androsten-Ufi-ol acetate and 2-benzoxymethyl-17a-ethyl-A -androsten-1713-01 acetate. By subsequent saponification ofthese compounds, in accordance with the method of Example X, there wereobtained the respective free compounds.

Exam'ple XVIII By following the method of acetylation described inExample III, 2-hydroxymethyl-17a-vinyl-A -androsten- 17 9-01 andZ-hydroxymethyl-17a-ethynyl-A -androsten- 175-01 were respectivelyconverted into 2-acetoxymethyl- 17a-vinyl-A -androsten-175-01 and2-acetoxymethyl-17aethynyl-A -androsten-175-01.

We claim:

1. A compound of the following formula:

Hi weak/l1 wherein R is selected from the group consisting of hydrogenand methyl; R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; R isselected from the group consisting of hydrogen, lower alkyl, loweralkenyl and lower alkynyl, and R is selected from the group consistingof hydrogen, lower alkyl and aralkyl containing up to eight carbonatoms.

2. 2-hydroxymethyl-M-androsten-l76-01.

3. 2-hydroxymethyl-17a-methyl-A -androsten-l7 8-01.

4. Z-hydroxymethyl-19-nor-A -androsten-175-01.

5. Z-hydroxymethyl-17a-vinyl-A -androsten-l75-01.

6. Z-hydroxymethyl-17u-ethynyl-A -androsten-175-01.

7. 2 hydroxymethyl 17a methyl 19 nor A androsten-17/3-ol.

8. 2 hydroxymethyl 17oz ethynyl 19 nor A androsten-l7p-ol.

9. The propionate of 2-propionoxymethyl-A -androsten-17fi-ol.

10. The caproate of Z-capronoxymethyl-M-androsten- 175-01.

11. 2-methoxymethyl-A -androsten-175-01.

12. Z-methoxymethyl-l7a-methyl-A -androsten-17,6-01.

13. The acetate of 2-111eth0xymethyl-A -androsten- 17/3-01.

14. 2-acetoxymethyl-17a-vinyl-A -androsten-17,6-01.

15. 2-acetoxymethyl-17a-ethynyl-A -androsten-17 3-01.

16. A process for preparing a compound of the following formula:

wherein R, R and R have the same meaning as above, with a double metalhydride to form the corresponding Z-hydroxymethyl compound andthereafter esterifying with a hydrocarbon carboxylic acid of less than12 carbon atoms.

17. A process for preparing a compound of the following formula:

of the following formula:

l---. g i

IUOHaC-l H wherein R and R have the same meaning as before and Rrepresents the hydrocarbon carboxylic acyl group of less than 12 carbonatoms, with a double metal hydride to form the corresponding2-hydroxymethyl compound and thereafter reacting the latter compoundwith an etherfying agent.

No references cited.

1. A COMPOUND OF THE FOLLOWING FORMULA: